The long-term goal of this grant is to develop new approaches to improve vascular repair, control angiogenesis and aid wound healing by understanding the biological function of tissue transglutaminase (TTG). TTG is a unique wound-healing enzyme that displays many important biologic activities often overlooked when studying wound healing. There are many gaps in our knowledge of TTG structure and function that we plan to systematically investigate in this grant application. In aim 1, we plan to investigate at what phase of wound healing TTG functions to promote tissue repair. In aim 2, we will examine at what phase of wound healing TTG expression and function is needed using the TTG KO mouse model.In aim3, we plan to investigate the role of the transglutaminase and NO binding activities of Mouse TTG on wound healing; and in aim 4, we plan to investigate whether TTG added to the fibrin chambers in a diabetic mouse model would overcome the documented wound healing defect that exists in diabetes mellitus. Understanding how TTG function in wound repair could lead to important advances in treating diseases such as diabetes with impair wound healing.